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The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism. 遗传病理生理学和 TAD 病(X-Linked Acrogigantism)的临床治疗。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-12 DOI: 10.1210/endrev/bnae014
Adrian F Daly, Albert Beckers

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein-coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

垂体巨人症是一种罕见的慢性生长激素(GH)过剩的表现,在生长板闭合之前就已开始。近一半的垂体巨人症患者有可确定的遗传原因。X 连锁渐冻人症(X-LAG;占垂体性巨人症的 10%)通常在婴儿期发病,可导致所述的最高个子。自发现以来的 10 年中,已发现约 40 名患者。X-LAG 患者通常会出现 GH 和催乳素混合型大腺瘤,偶尔会出现增生,分泌大量 GH,并经常分泌催乳素。一部分患者的循环 GH 释放激素(GHRH)也会升高。X-LAG是由染色体Xq26.3上的组成型或偶发性镶嵌复制引起的,这种复制破坏了孤儿G蛋白偶联受体(GPCR)GPR101周围拓扑关联域(TAD)的正常染色质结构。这就导致了新TAD的形成,其中GPR101的过度表达是由异位增强子驱动的("TADopathy")。由于受影响的母亲将复制传给了儿子,在三个家族中出现了 X-LAG。GPR101 是一种具有未知天然配体的组成型活性受体,它通过多种 G 蛋白和蛋白激酶 A 和 C 发出信号,促进 GH/泌乳素分泌过多。X-LAG 的治疗具有挑战性,因为患者年龄较小,而且对体生长激素类似物具有抗药性;GH 受体拮抗剂 pegvisomant 通常是一种有效的选择。GH、胰岛素样生长因子1(IGF-1)和催乳素分泌过多以及身体过度生长可以在明确的成人巨人症发生之前得到控制,但代价往往是永久性的垂体功能减退。
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引用次数: 0
Relative Energy Deficiency in Sport (REDs): Endocrine Manifestations, Pathophysiology and Treatments. 运动中的相对能量缺乏症(REDs):内分泌表现、病理生理学和治疗方法。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-12 DOI: 10.1210/endrev/bnae011
Angeliki M Angelidi, Konstantinos Stefanakis, Sharon H Chou, Laura Valenzuela-Vallejo, Konstantina Dipla, Chrysoula Boutari, Konstantinos Ntoskas, Panagiotis Tokmakidis, Alexander Kokkinos, Dimitrios G Goulis, Helen A Papadaki, Christos S Mantzoros

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

对瘦弱、能量缺乏的运动员和军人群体的研究,将女性运动员三联征的概念扩展为运动中相对能量缺乏(REDs)综合征。REDs 代表了低能量可用性(LEA)诱发的一系列异常现象,是 REDs 概念中描述的所有症状的根本原因,影响着任何生理性别的运动人群。短期和长期的 LEA 与其他调节因素相结合,可产生多种不适应变化,损害各种生理系统,并对健康、福祉和运动表现产生不利影响。因此,REDs 的综合定义涵盖了与 LEA 相关的一系列生理后遗症和不良临床结果,如神经内分泌、骨骼、免疫和血液学影响,最终导致健康和运动表现受损。在本综述中,我们将讨论 REDs 及其相关疾病的病理生理学。我们简要研究了目前针对 REDs 的治疗建议,主要侧重于针对其根本原因--能量不足--的非药物、行为和生活方式的调整。我们还讨论了旨在控制月经功能障碍和骨应力损伤等症状的治疗方法,并探讨了针对潜在生理机制的潜在新型疗法,强调了瘦素和激活素-花粉抑制素轴在 REDs 病理生理学和治疗中的作用,这些作用仍有待全面阐明。在不久的将来,利用我们对能量可用性或缺乏能量可用性的分子和生理轴的新认识,新型疗法可能会恢复与 LEA 相关的异常,从而预防和/或治疗与 REDs 相关的健康并发症,如应力性骨折,并改善运动表现。
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引用次数: 0
Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors. 鸟苷酸环化酶 (GC)-A 和其他膜 GC 受体的磷酸化依赖性调控
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-12 DOI: 10.1210/endrev/bnae015
Lincoln R Potter

Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on 4 to 7 conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E, and sea urchin receptors are discussed, as are mutant receptors that mimic the dephosphorylated inactive or phosphorylated active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases, and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long-bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future.

受体鸟苷酸环化酶(GCs)是一种跨膜的多域酶,可在钠尿肽或其他配体的作用下合成 cGMP。从海胆到人类,它们在进化过程中保持一致,并调节着不同的生理机能。大多数家族成员在其激酶同源结构域起始处的四到七个保守丝氨酸或苏氨酸上被磷酸化。本综述介绍了证明这些酶的激活和失活分别需要磷酸化和去磷酸化的研究。本文讨论了 GC-A、GC-B、GC-E 和海胆受体中的磷酸化位点,以及分别模拟 GC-A 和 GC-B 的去磷酸化、非活性或磷酸化、活性形式的突变受体。描述的盐桥模型解释了酶激活需要磷酸化的原因。还讨论了 GC 受体的潜在激酶、磷酸酶和 ATP 调节。重要的是,描述了受体磷酸化位点被谷氨酸取代的基因敲入小鼠。在 GC-A 或 GC-B 不能去磷酸化的小鼠中,相反的信号通路不能抑制 cGMP 合成,这证明了体内受体去磷酸化的必要性。心脏肥大、卵母细胞减数分裂、长骨生长/软骨增生和骨密度受 GC 磷酸化调节,但未来可能还会发现其他过程。
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引用次数: 0
Cardiometabolic Aspects of Congenital Adrenal Hyperplasia. 先天性肾上腺皮质增生症的心脏代谢问题
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-06 DOI: 10.1210/endrev/bnae026
Robert Krysiak, Hedi L Claahsen-van der Grinten, Nicole Reisch, Philippe Touraine, Henrik Falhammar

Treatment of classic congenital adrenal hyperplasia (CAH) is directed at replacing deficient hormones and reducing androgen excess. However, even in the era of early diagnosis and lifelong hormonal substitution, the presence of CAH is still associated with numerous complications and also with increased mortality. The aim of this article was to create an authoritative and balanced review concerning cardiometabolic risk in patients with CAH. The authors searched all major databases and scanned reference lists of all potentially eligible articles to find relevant articles. The risk was compared with that in other forms of adrenal insufficiency. The reviewed articles, most of which were published recently, provided conflicting results, which can be partially explained by differences in the inclusion criteria and treatment, small sample sizes and gene-environmental interactions. However, many studies showed that the presence of CAH is associated with an increased risk of weight gain, worsening of insulin sensitivity, high blood pressure, endothelial dysfunction, early atherosclerotic changes in the vascular wall and left ventricular diastolic dysfunction. These complications were more consistently reported in patients with classic than non-classic CAH and were in part related to hormonal and functional abnormalities associated with this disorder and/or to the impact of over- and undertreatment. An analysis of available studies suggests that individuals with classic CAH are at increased cardiometabolic risk. Excess cardiovascular and metabolic morbidity is likely multifactorial, related to glucocorticoid overtreatment, imperfect adrenal hormone replacement therapy, androgen excess and adrenomedullary failure. Cardiometabolic effects of new therapeutic approaches require future targeted studies.

治疗典型的先天性肾上腺增生症(CAH)的目的是补充缺乏的激素,减少雄激素过多。然而,即使在早期诊断和终身激素替代的时代,CAH 的存在仍然与众多并发症和死亡率的增加有关。本文旨在就 CAH 患者的心脏代谢风险撰写一篇权威、平衡的综述。作者检索了所有主要数据库,并扫描了所有可能符合条件的文章的参考文献目录,以找到相关文章。将其风险与其他形式肾上腺功能不全的风险进行了比较。所查阅的文章大多是近期发表的,其结果相互矛盾,部分原因可能是纳入标准和治疗方法不同、样本量较小以及基因与环境之间存在相互作用。然而,许多研究表明,CAH 的存在与体重增加、胰岛素敏感性恶化、高血压、内皮功能障碍、血管壁早期动脉粥样硬化变化和左心室舒张功能障碍的风险增加有关。据报道,这些并发症在典型 CAH 患者中的发生率高于非典型 CAH 患者,部分原因与该疾病相关的激素和功能异常和/或过度治疗和治疗不当的影响有关。对现有研究的分析表明,典型 CAH 患者的心血管代谢风险增加。过高的心血管和代谢发病率可能是多因素的,与糖皮质激素过度治疗、不完善的肾上腺激素替代治疗、雄激素过多和肾上腺髓质功能衰竭有关。未来需要对新的治疗方法对心脏代谢的影响进行有针对性的研究。
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引用次数: 0
Postbiotic impact on host metabolism and immunity provides therapeutic potential in metabolic disease. 后生物对宿主新陈代谢和免疫的影响为代谢性疾病的治疗提供了潜力。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-05 DOI: 10.1210/endrev/bnae025
Han Fang, Rodrigo Rodrigues E-Lacerda, Nicole G Barra, Dana Kukje Zada, Nazli Robin, Alina Mehra, Jonathan D Schertzer

The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds such as lipopolysaccharides, muropeptides can have opposing effects on endocrine control of host metabolism where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites such as short chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.

肠道微生物群会影响代谢疾病的各个方面,包括组织炎症、脂肪、血糖、胰岛素和代谢的内分泌控制。人们通常寻求益生元或益生菌来防治代谢性疾病。然而,益生元缺乏特异性,可能会对细菌群落产生有害影响。益生菌需要活细菌找到足以影响宿主免疫或新陈代谢的定植位点。后益生菌包括细菌衍生的成分和分子,它们能够很好地改变宿主的免疫代谢,而不依赖于定植效率或对现有微生物群造成广泛影响。在此,我们总结了与代谢性疾病相关的特定益生菌后的潜在有益和有害影响,以及其潜在的作用机制。细菌细胞壁成分(如脂多糖、微肽、脂亮酸和鞭毛蛋白)通过调动特定的免疫反应对宿主的新陈代谢产生环境依赖性影响。在脂多糖、微肽等大类化合物中,特定类型的益生元可对宿主代谢的内分泌控制产生相反的影响,其中某些益生元是胰岛素增敏剂,而其他益生元则会促进胰岛素抵抗。短链脂肪酸、胆汁酸、乳酸、甘油、琥珀酸、乙醇胺和乙醇等细菌代谢产物可以成为宿主代谢的底物。益生菌后可直接促进宿主的新陈代谢途径,或通过免疫调节或模拟宿主衍生的激素影响内分泌对新陈代谢的控制。在代谢性炎症和代谢性疾病期间,应考虑后生菌在宿主-微生物关系中的相互作用。
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引用次数: 0
The cortisol awakening response: regulation and functional significance. 皮质醇觉醒反应:调节和功能意义。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-23 DOI: 10.1210/endrev/bnae024
Tobias Stalder, Henrik Oster, James L Abelson, Katharina Huthsteiner, Tim Klucken, Angela Clow

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30-45 min after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid non-genomic and slower genomic pathways (e.g., affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.

对于健康人来说,大部分皮质醇分泌发生在早晨醒来后的几个小时内。皮质醇唤醒反应(CAR)是这一分泌期中研究较多的一个组成部分,即皮质醇水平在早晨醒来后的前 30-45 分钟内迅速增加。活跃期开始时皮质醇的这种强烈迸发被认为是机体为迎接即将到来的一天的挑战做好准备的功能。在此,我们回顾了有关 CAR 关键调节和功能过程的证据,并对其功能作用建立了一个综合模型。具体来说,我们提出,在健康人体内,CAR 受到一个复杂的双重控制系统的密切调控,该系统利用关键的昼夜节律、环境和神经认知过程来最好地预测每日对皮质醇相关作用的需求。微调的 CAR 表达反过来又会通过快速的非基因组和较慢的基因组途径(如影响昼夜节律钟基因表达)诱导有效的糖皮质激素作用,从而通过相关的代谢、免疫和神经认知系统支持和调节日常活动。我们认为,这种协同作用在调解两个主要功能方面具有适应性:一个主要过程是调动资源以满足与活动有关的需求,另一个次要过程是帮助机体反调节前一天的不良情绪体验。
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引用次数: 0
Structure and Function of Somatostatin and its Receptors in Endocrinology. 内分泌学中的促生长素及其受体的结构和功能。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-08 DOI: 10.1210/endrev/bnae022
Bo Zhang, Li Xue, Zhe Bao Wu

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

奥曲肽 (OCT)、兰雷奥肽和帕司雷奥肽等体生长抑素类似物作为体生长抑素受体配体 (SRL) 起作用,是治疗肢端肥大症的主要药物。这些配体也是神经内分泌肿瘤(NET)放射治疗和成像的重要分子。体生长抑素受体(SSTRs)是典型的 G 蛋白偶联蛋白(GPCRs),在新陈代谢、生长以及激素紊乱、神经系统疾病和癌症等病理情况中发挥作用。低温电子显微镜(cryo-EM)结合蛋白质结构预测平台 AlphaFold 已被用于确定许多蛋白质的三维结构。最近,几个研究小组发表了一系列论文,展示了 SSTR2 的三维结构,包括与不同配体结合的非活性/活性 SSTR2-G 蛋白复合物的三维结构。研究结果揭示了有助于配体结合袋的残基,并证明体生长抑素类似物中的 Trp8-Lys9(W-K 基团)是稳定结合袋底部的关键基团。在这篇综述中,我们将讨论有关 SSTR 和 SRL 结构分析的最新发现、结构数据与临床发现之间的关系以及基于结构的新型疗法的未来发展。
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引用次数: 0
Adiponectin and Adiponectin Receptors in Atherosclerosis. 动脉粥样硬化中的脂肪连接素和脂肪连接素受体
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-06 DOI: 10.1210/endrev/bnae021
Ioanna Gianopoulos, Christos S Mantzoros, Stella S Daskalopoulou

Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between pro-inflammatory responders, and anti-inflammatory pro-resolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 pro-inflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift towards an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the impact of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.

脂肪连通素是一种大量分泌的激素,可在脂肪组织、免疫系统和心血管系统之间传递信息。在新陈代谢健康的人体内,脂肪连通素的含量通常很高,有助于改善外周组织对胰岛素的反应、葡萄糖耐量和脂肪酸氧化。除了在胰岛素敏感组织中发挥新陈代谢功能外,脂肪连通素还部分通过调节巨噬细胞介导的反应,在减少动脉粥样硬化斑块的形成方面发挥着重要作用。在这种情况下,脂肪连通素与其受体--巨噬细胞细胞表面的脂肪连通素受体 1(AdipoR1)和 AdipoR2 结合,激活下游信号级联,诱导特定的动脉粥样硬化保护功能。值得注意的是,巨噬细胞通过在促炎症反应介质和抗炎症促溶解介质之间切换的能力来调节斑块的稳定性。传统上,巨噬细胞极化谱的两极包括 M1 促炎表型和 M2 抗炎表型。以往的证据表明,脂肪连通素-AdipoR通路影响着M1-M2巨噬细胞的极化;脂肪连通素促进向类似M2的状态转变,而AdipoR1-和AdipoR2-特异性的贡献则更为细微。为了深入探讨这些概念,我们在这篇综述中讨论了脂肪连接素和 AdipoR1/R2 对 1)代谢和免疫反应以及 2)M1-M2 巨噬细胞极化的影响,包括它们减轻动脉粥样硬化斑块炎症的能力,以及它们作为临床应用治疗靶点的潜力。
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引用次数: 0
Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement. 小青春期,生理性和失调性:后果和治疗替代的潜力。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae003
Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, Sasha R Howard

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

在人的一生中,下丘脑-垂体-性腺轴(HPG)的中枢活动有三个生理波段。第一波发生在胎儿时期,第二波被称为 "小青春期",发生在出生后的头几个月,第三波发生在青春期。青春期过后,该轴在整个成年期都会保持活跃。先天性性腺功能减退症(CHH)是一种罕见的遗传性疾病,其特点是下丘脑促性腺激素释放激素(GnRH)分泌或作用不足。在严重的 CHH 病例中,GnRH 的三波搏动都不存在。胎儿 HPG 轴激活缺失表现为约 50% 的男性新生儿有小阴茎和/或睾丸下降不全(隐睾症)。在这些男孩中,小青春期的缺失凸显了睾丸的不成熟。其特点是塞尔托利细胞数量少,而塞尔托利细胞对未来的生殖能力非常重要。因此,小青春期的缺失将对这些男性日后的生育能力产生不利影响。婴儿 CHH 的诊断常常被漏诊,即使确诊,最佳治疗方法也没有达成共识。在此,我们回顾了生理性小头畸形和 HPG 轴中枢紊乱的后果;提供了一种诊断方法,以便及早发现这些病症;并回顾了目前替代 CHH 男婴小头畸形的治疗方案。有小型病例系列的证据表明,用促性腺激素替代来模拟男性的 "小青春期 "不仅在睾丸下降方面有益,而且还能使睾丸和阴茎大小正常化。此外,对发育紊乱的 "小青春期 "采取这种治疗替代方案,可以解决生殖和非生殖方面的问题。
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引用次数: 0
Genetic and Epigenetic Landscape for Drug Development in Polycystic Ovary Syndrome. 多囊卵巢综合症药物开发的基因和表观遗传学前景。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae002
Yi Chen, Guiquan Wang, Jingqiao Chen, Congying Wang, Xi Dong, Hsun-Ming Chang, Shuai Yuan, Yue Zhao, Liangshan Mu

The treatment of polycystic ovary syndrome (PCOS) faces challenges as all known treatments are merely symptomatic. The US Food and Drug Administration has not approved any drug specifically for treating PCOS. As the significance of genetics and epigenetics rises in drug development, their pivotal insights have greatly enhanced the efficacy and success of drug target discovery and validation, offering promise for guiding the advancement of PCOS treatments. In this context, we outline the genetic and epigenetic advancement in PCOS, which provide novel insights into the pathogenesis of this complex disease. We also delve into the prospective method for harnessing genetic and epigenetic strategies to identify potential drug targets and ensure target safety. Additionally, we shed light on the preliminary evidence and distinctive challenges associated with gene and epigenetic therapies in the context of PCOS.

多囊卵巢综合症(PCOS)的治疗面临挑战,因为所有已知的治疗方法都只是对症治疗。美国食品和药物管理局(FDA)尚未批准任何专门用于治疗多囊卵巢综合症的药物。随着遗传学和表观遗传学在药物开发中的重要性不断提高,它们的重要见解大大提高了药物靶点发现和验证的效率和成功率,为指导多囊卵巢综合症治疗的进步带来了希望。在此背景下,我们概述了多囊卵巢综合症的遗传学和表观遗传学进展,这些进展为这一复杂疾病的发病机制提供了新的见解。我们还深入探讨了利用基因和表观遗传学策略识别潜在药物靶点并确保靶点安全性的前瞻性方法。此外,我们还阐明了与多囊卵巢综合症相关的基因和表观遗传疗法的初步证据和独特挑战。
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引用次数: 0
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Endocrine reviews
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